The active ingredients, contained in medicinal products, can be available in polymorphous forms having different chemical-physical properties, as for example solubility and chemical stability.
For medicinal products both these properties are critical for the in vivo absorption of the active ingredient, and consequently, for the efficacy and safety of the product after administration in humans or animals.
A large number of scientific papers is available on this topic. Some articles are for example: doxazosin (Sohn Y. T. et al., Arch. Pharm. Res., 2005; 28, 730-735); tranilast (Vogt F. G. et al., J. Pharm. Sci., 2005, 94, 651-65); clopidogrel (Koradia V., et al., Acta. Pharm., 2004, 54 (3), 193-204); celecoxib (Chawla G. et al., Pharm. Dev. Technol., 2004, 9 (4), 419-33); ketorolac (Sohn Y. T. et al., Arch. Pharm. Res. 2004, 27 (3), 357-60); fluconazol (Caira M. R. et al., J. Pharm. Sci., 2004, 93 (3), 601-11); piroxicam (Vrecer F. et al., Int. J. Pharm., 2003, 256 (1-2), 3-15); theophylline (Airaksinen S. et al., Int. J. Pharm., 2004, 276 (1-2), 129-41).
For the above mentioned reasons the medical authority responsible for the approval of the marketing of medicinal products requires information on the properties and the production consistency of the polymorphous active ingredients in the solid state; it is important to avoid modification of the polymorphous form during the production stage and storage of the pharmaceutical preparation. For this purpose, it is important to select from among all the possible polymorphous forms those showing the highest stability in time, as described by Rodriguez-Spong B. et al. in Adv. Drug Deliv. Rev., 2004, 56 (3), 241-74.
To obtain a more stable polymorphous form, saline active ingredients are often used, as described in Adv. Drug Del. Rev., 2006, 56, 231-334.
Rifaximin is an antibiotic belonging to the rifampicin family, available in tablets, granules for oral suspension and ointment, marketed in Europe, in the U.S.A. and in many other countries.
Rifaximin can exist in the polymorphous forms α, β and γ described by Viscomi G. C. et al. in IT MI2003 A 002144, (2003) and U.S. Pat. No. 7,045,620 B1, (2003), and in the polymorphous forms δ and ε described by Viscomi G. C. et al. in EP 1698630 (2005). These polymorphous forms are very important because they can change the intrinsic dissolution by approximately ten times and the bioavailability of rifaximin by almost six hundred times, as described by Viscomi et al. in WO 2005/044823 (2004). These changes can have a strong effect on the efficacy and the safety of the product.
Moreover it is known from U.S. Pat. No. 7,045,620 B1, (2003) and EP 1698630 (2005) that the rifaximin polymorphous forms can easily convert into other forms depending on the possibility to acquire or to lose water. These transformations can occur also in the solid state, because of changes in humidity and temperature conditions. For example in environments with a relative humidity around 50% or higher, polymorph α converts into polymorph β. Another example is represented by polymorph ε, that can be obtained by drying polymorph δ, as described in EP 1698630 (2005) and that shows a twenty fold reduction of bioavailability compared to the δ form.
The different rifaximin polymorphous forms can be favourably used as homogeneous and pure products in the manufacturing of the medicinal products containing rifaximin, as the efficacy and the safety of the product can be modulated by using the right polymorphous form.
The prior art allows to understand the importance of the production conditions of the medicinal products containing rifaximin, which, in case they are not opportunely controlled, can give undesirable transformations of the rifaximin polymorphous forms.
Moreover, also working phases used in the pharmaceutical product production and involving the use of water, for example powder granulation under humid conditions, film coating process with water as solvent, drying, can modify the polymorphous form of the chosen rifaximin. Also the storage of rifaximin and of the medicinal product containing it can cause problems since humidity may modify the polymorphous form in time; thus particular attention has to be paid to manufacturing.
As previously described it is advantageous from the industrial point of view to have polymorphous forms of rifaximin under conditions independent of the environment humidity to permit the production with the water removal without modifying the polymorphism.